facile synthesis, characterization and in silico docking

Rwanda Journal of Engineering, Science, Technology and Environment, Volume 4, Issue 1, June 2021

eISSN: 2617-233X | print ISSN: 2617-2321

1

https://dx.doi.org/10.4314/rjeste.v4i1.5

Facile Synthesis, Characterization and in Silico Docking Studies of Novel

Thiazolidine-2,4-Dione-Based Mannich Base Bearing Furan/Thiophene

Moiety as Promising Anti-Inflammatory Agents

Jean Baptiste Nkurunziza1*, Pierre Dukuziyaturemye2, Edith Musabwa 2, Balakrishna Kalluraya3

1Department of Mathematics, Science and Physical Education, College of Education, University of Rwanda,

P.O.Box: 55 Rwamagana, Rwanda 2Department of Environmental Health Sciences, College of Medicine and Health Sciences, University of Rwanda,

P.O.Box 3286, Kigali, Rwanda 3Department of Studies in Chemistry, Mangalore University, Mangalagangothri-574199, Karnataka, India.

*Corresponding Author: [email protected]

DOI: 10.4314/rjeste.v4i1.5


Abstract

Mannich bases are compounds bearing a β-amino carbonyl moiety. They are formed in the

Mannich reaction that consists of an amino alkylation of an acidic proton placed next to a

carbonyl functional group by formaldehyde and a primary or secondary amine. Mannich base

products are known for their curative properties such as anti-inflammatory, antibacterial,

anticancer, antifungal, anthelmintic, anticonvulsant, analgesic, anti-HIV, antipsychotic, antiviral,

and antimalarial activities. Further, thiazolidinedione derivatives have shown to be efficacious in

inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic

steatohepatitis. In light of the above observations, new series of thiazolidine-2,4-dione based

Mannich base derivatives were synthesized via a simple and catalyst-free procedure involving

the condensation of thiazolidine-2,4-dione, formaldehyde and secondary amines in DMF solvent.

The structures of the newly synthesized compounds were confirmed by their IR, 1H-NMR, and

Mass spectra. The synthesized compounds were tested for their in silico anti-inflammatory

activity by Docking studies against COX-2 enzyme (PDB: 1CX2). Compounds 4a and 4b

showed good in silico anti-inflammatory properties comparable to that of standard drug

Diclofenac and may be considered as promising candidates for the development of new anti-

inflammatory agents.


mailto:[email protected]




2


Keywords: Anti-inflammatory agents; Docking studies; Furan; Thiazolidine-2,4-dione;

Thiophene.

1. Introduction

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment and

management of inflammation and pain associated with conditions such as osteoarthritis,

rheumatoid arthritis, post-operative pain, orthopedic injuries, ankylosing spondylitis, gout,

dysmenorrhea, dental pain and headache (Atzeni et al., 2018; Ong et al., 2007). Non-steroidal

anti-inflammatory drugs are divided into two categories: non-selective inhibiting both

cyclooxygenase enzymes COX-1 and COX-2, and selective inhibiting COX-2 enzyme (Brune

and Patrignani, 2015). Although COX-1 and COX-2 are isoenzymes involved in the same

physiological pathway converting arachidonic acid (AA) to prostaglandins (PDs) (Bakhle, 1999;

Meek et al., 2010), COX-1 isoenzyme is a constitutive enzyme mainly found in the

gastrointestinal lining with a “house-keeping” role in regulating many normal physiological

processes in which prostaglandins serve a protective role (Fokunang et al., 2018), though COX-2

enzyme is facultative, and expressed at the sites of inflammation by pro-inflammatory molecules

such as interleukin-1 (IL-1), tumor necrosis factor- (TNF-), lipopolysaccharide (LPS), and tissue

plasminogen activator (TPA) (Fokunang et al., 2018; B Bari and D Firake, 2016) and produces

the desirable effects of NSAIDs (Zarghi and Arfaei, 2011). For the reasons stated above, long

term uses of non-selective NSAIDs is not advisable due to their severe gastrointestinal toxicities

(Rodríguez and González-Pérez, 2005; Vostinaru, 2017), resulting from their stronger inhibition

of COX-1 enzyme (Vostinaru, 2017). Examples of NSAIDs that were removed from the market

due to their toxicities include Vioxx (rofecoxib) pulled from the worldwide market due to its

increased risk for heart attacks and strokes (Sibbald, 2004); Bromfenac, Ibufenac, and

Benoxaprofen that were reported to be hepatotoxic (Goldkind, 2006). Therefore, the present

work intends to search for novel safe and selective COX-2 inhibitors for the management of pain

and inflammation.

Thiazolidine-2,4-dione (TZD) derivatives were reported to exhibit diverse pharmacological

properties such as anti-tubercular (Chilamakuru et al., 2013), antidiabetic, antimicrobial and anti-

cancer (Durai Ananda Kumar et al., 2015). Recently, it was reported that TZD derivatives are




3


potent anti-inflammatory agents (Srivastava et al., 2019). In the study conducted by Zhu et al.

(2011), TZDs inhibited the release of a variety of inflammatory mediators from human Airway

Smooth Muscle cells, suggesting their uses in the treatment of asthma. Ceriello (2007) reviewed

the anti-inflammatory activity of TZDs and found that these compounds act by modulating the

anti-inflammatory markers such as IL-6, IL-18, CRP, MMP-2, MMP-9. Mohanty et al. (2004)

evidenced the anti-inflammatory effect of rosiglitazone as a drug of the thiazolidinedione class

that exerts an anti-inflammatory effect at the cellular and molecular level, and in plasma. In

addition to these useful properties of thiazolidinedione products; furan and thiophene derivatives

form a class of compounds with a broad spectrum of biological properties such as antibacterial

(Holla et al., 1987), anti-allergic, antidepressant, antidiabetic, analgesic and anti-inflammatory

activities (Mishra et al., 2011).

Nowadays, in silico molecular docking studies of small molecules to protein binding sites has

become an increasingly popular approach for the development of new drugs (Berry et al., 2015).

This is because in silico molecular docking study requires very less time to differentiate from

many compounds the most probable potent ones with desired biological activities when

compared with traditional laboratory experiments (Naim et al., 2018; Afriza et al., 2018). In view

of the above prominent properties of thiazolidinedione, furan and thiophene derivatives and rapid

with higher precision of in silico docking studies, novel series of compounds incorporating both

thiazolidine-2,4-dione and furan/thiophene moieties in one Mannich base molecule that might

display synergetic and enhanced biological activities were synthesized, characterized and

evaluated for their in silico COX-2 inhibitory activity.

2. Material and methods

2.1. Material

The innovative DTC-967A apparatus was used to determine the melting points of the new

compounds and are uncorrected. The IR-spectra (in KBr pellets) were recorded on Shimadzu FT-

IR Prestige-21 spectrophotometer and are expressed in cm-1. The mass spectra were recorded on

Shimadzu LC-MS-8030 mass spectrophotometer operating at 70 eV. A Bruker AVANCE II 400

MHz instrument was used to record 1H-NMR spectra in CDCl3 as solvent and TMS as an

internal standard.




4


2.2. Chemistry method

Thiazolidine-2,4-dione (1) was synthesized by the cyclocondensation of thiourea with

monochloroacetic acid in acidified water solvent (Kar et al., 2014). Knoevenagel condensation of

thiazolidine-2,4-dione (1) with furan/thiophene-5-carbaldehyde (2) in ethanol solvent containing

a catalytic amount of piperidine afforded the key intermediate: furfurylidene/thienylidene

thiazolidine-2,4-dione (3) prepared according to Ha et al. (2012). Novel Mannich base products

(4) were synthesized by reacting compounds (3) with formaldehyde and secondary amines:

piperidine, morpholine or N-methylpiperazine (Scheme 1) in DMF solvent as given in the

general procedure. The completion of the reaction, as well as the purity of the products (4), were

checked by TLC using silica gel plates (Merck) with hexane:ethylacetate (6:4) as mobile phase.

Scheme 1: Synthesis of Mannich base derivatives of thiazolidinedione

Synthesis of 5-(furan-2/thiophen-2-ylmethylene)thiazolidine-2,4-dione-based Mannich

bases (4a-e): General procedure

Furfurylidene/thienylidene thiazolidine-2,4-dione (3) (0.01 mol) and formaldehyde (40%, 1.5

mL) were added in 100 mL Erlenmeyer flask containing 10 mL DMF. Using a magnetic stirrer,

the mixture was stirred at room temperature for 20 min. An appropriate secondary amine (0.01

mol): piperidine / morpholine / N-methyl piperazine was then added, and the resulting mixture




5


was further stirred at room temperature for 6 hours to precipitate Mannich base products that

were collected by filtration, washed with cold water, dried and recrystallized from ethanol.

2.3. Molecular Docking Studies

In silico docking study was performed according to Rizvi et al. (2013) to predict interactions of

newly synthesized compounds (4a-e) with the target COX-2 enzyme's active site. The crystal

structure of COX-2 (PDB code: 1CX2) was downloaded from RCSB Protein Data Bank

(http://www.rcsb.org) as 1CX2.PDB (gz). It was then processed using Discovery Studio Biovia

2020 suite (Dassault Systèmes, San Diego, California, USA) in which protein inhibitor SC558,

all water molecules, unwanted heteroatoms and similar chains B, C and D were deleted to

generate the file saved as 1CX2.PDB. This file was further processed by adding polar hydrogen

atoms and Kollman Charges to the individual protein atoms with Auto Dock Tool (ADT)

software to get 1CX2.PDBT file required for Autogrid and AutoDock (Huey and Morris, 2008);

Rizvi et al., 2013).

The Marvin Sketch software (Marvin suite 20.11.0) was used for drawing and energy

minimization of each ligand structure (4a-e) to generate ligand.PDB. The ADT was then used to

process these ligands in which nonpolar hydrogens were combined, Gasteiger changes and

rotatable bonds were added and generated ligand.PDBQT format needed by Autogrid and

Autodock (Rizvi et al., 2013; Morris, 2012). Autogrid parameters were set using ADT and a

docking grid box was built with 40, 40, and 40 points in X, Y and Z dimensions with X=31.594,

Y=24.653, and Z=12.650 as the position of the active site to generate a.GPF file. A docking

parameter file a.DPF was prepared using the Lamarckian genetic algorithm 4.2 search method

implemented in AutoDock 4.2 software integrated within Auto Dock Tools version 1.5.6 (ADT;

Scripps Research Institute, La Jolla, San Diego, USA). The receptor was kept rigid, ligands were

allowed to be flexible and all docking parameters were set to default. The molecular docking was

performed on Microsoft windows 10, 64-bit laptop using Cygwin software. The docking results

were analyzed by Discovery Studio Biovia 2020 suite software.




6


3. Results and discussion

3.1. Chemistry

The structures of newly synthesized compounds 5-(furan-2/thiophen-2 ylmethylene)thiazolidine-

2,4-dione-based Mannich compounds (4a-e) were confirmed by their IR, 1H-NMR, and mass

spectra. Other data that characterize the newly synthesized compounds are given in Table 1.

Table 1: Characterization data of synthesized thiazolidinedione based Mannich bases (4a-e).

Compd.

No.

X Y M.P (oC)

(Yield %)

Molecular

formula

Mol. Wt Chemical structure

4a O CH2 189-191

(82)

C14H16N2O3S 292.35

4b S CH2 220-222

(74)

C14H16N2O2S2 308.41

4c S O 198-200

(76)

C13H14N2O3S2 310.39

4d S N-CH3 206-208

(72)

C14H17N3O3S 307.37

4e O O 176-178

(68)

C13H14N2O4S 294.33

The table above gives the melting point: M.P (oC), molecular formula, molecular weight (Mt),

and the chemical structure of the newly synthesized compounds 4a-4e. The results from the




7


above table show that the newly synthesized compounds were formed in a good yield ranging

from 68% to 82% with molecular weight between 292 to 310.

The IR spectrum of 5-(furan-2-ylmethylene)-3-(piperidin-1-ylmethyl)thiazolidine-2,4-dione (4a)

(Figure 1) showed prominent bands at 3089 cm-1 and 2964 cm-1 for C-H stretching frequencies.

The bands at 1645 cm-1 and 1589 cm-1 are attributed for C=O stretching frequencies, while the

C-O band appeared at 1273 cm-1 stretching frequency.

Figure 1: The IR spectrum of 5-(furan-2-ylmethylene)-3-(piperidin-1-ylmethyl)thiazolidine-2,4-

dione (4a)

The formation of Mannich base products (4a-e) from compounds (3) was further confirmed by

their 1H NMR spectra. As a typical example, in the 1H-NMR (400 MHz, CDCl3) spectrum of 5-

(furan-2-ylmethylene)-3-(piperidin-1-ylmethyl)thiazolidine-2,4-dione (4a) (Figure 2) the

protons at the 4th position of piperidine moiety labelled as HA appeared as a quintet at δ 1.33-1.39

ppm integrating for two protons. A quintet signal seen at δ 1.52-1.58 ppm is due to the resonance




8


of four protons (HB) located at the 3rd position of piperidine moiety. The four protons (HC) from

the 2nd position of the piperidine group resonated as a triplet at δ 2.59-2.62 ppm while methylene

N-CH2-N protons (HD) came into resonance as a singlet at δ 4.69 ppm integrating for two

protons. One proton (HG) at the 4th position of furan ring come into resonance as a triplet at δ

6.57-6.58 ppm, whereas a doublet seen δ 6.77-6.78 ppm (J = 3.48 Hz) resulted from the

resonance of a proton (HF) located at the 3rd position of furan ring. The CH=C proton (HE)

resonated as a singlet at δ 7.62 ppm, and a proton (HI) at 5th position of furan ring appeared as a

doublet at δ 7.66-7.67 ppm (J = 1.64 Hz).

Figure 2: 1H NMR spectrum of 5-(furan-2-ylmethylene)-3-(piperidin-1-ylmethyl)thiazolidine-

2,4-dione (4a).

The mass spectra further confirmed the structures of the new compounds (4a-e). In a typical

example, the mass spectrum of 5-(furan-2-ylmethylene)-3-(piperidin-1-ylmethyl)thiazolidine-




9


2,4-dione (4a) (Figure 3) showed molecular ion peak at m/z = 292 (M+) which is in conformity

with its molecular formula C14H16N2O3S.

Figure 3: Mass spectrum of of 5-(furan-2-ylmethylene)-3-(piperidin-1-ylmethyl)thiazolidine-

2,4-dione (4a)

The spectral data of other newly synthesized compounds prepared according to the general

procedure presented in section 2.2 are given below:

4b) 3-(Piperidin-1-ylmethyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione

IR (KBr, γ/cm-1): 3074, 2985 (C-H stretch), 1633, 1573 (C=O stretch), 1H-NMR (400 MHz,

CDCl3): δ (ppm) 1.34-1.40 (quintet, 2H at 4th position piperidine), 1.52-1.58 (quintet, 4H at 3rd

position of piperidine), 2.60-2.63 (t, 4H at 2nd position of piperidine), 4.71 (s, 2H, N-CH2-N),

7.17-7.20 (t, 1H, furan-4H), 7.39-7.40 (d, J=3.64 Hz, 1H, furan-3H), 7.64-7.66 (d, J=5.08 Hz,

1H, furan-5H), 8.04 (s, 1H, C=CH). LC-MS (m/z): 309 (M+ + 1).




10


4c) 3-(Morpholinomethyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione


CDCl3): δ (ppm) 2.66-2.68 (t, 4H adjacent to N-morpholine), 3.66-3.68 (t, 4H adjacent to O-

morpholine), 4.70 (s, 2H, N-CH2-N), 7.18-7.21 (t, 1H, furan-4H), 7.40-7.41 (d, J=3.68 Hz, 1H,

furan-3H), 7.66-7.67 (d, J=5.04 Hz, 1H, furan-5H), 8.06 (s, 1H, C=CH). LC-MS (m/z): 310

(M+).

4d) 5-(furan-2-ylmethylene)-3-((4-methylpiperazin-1-yl)methyl)thiazolidine-2,4-dione


CDCl3): δ (ppm) 2.25 (s, 3H, N-CH3), 2.41 (s, 4H of piperazine moiety), 2.72 (s, 4H of

piperazine moiety), 4.73 (s, 2H, N-CH2-N), 7.18-7.20 (t, 1H, furan-4H), 7.39-7.40 (d, J=3.72 Hz,

1H, furan-3H), 7.65-7.66 (d, J=5.00 Hz, 1H, furan-5H), 8.03 (s, 1H, C=CH). LC-MS (m/z): 323

(M+).

4e) 5-(furan-2-ylmethylene)-3-(morpholinomethyl)thiazolidine-2,4-dione


CDCl3): δ (ppm) 2.65-2.68 (t, 4H adjacent to N-morpholine), 3.66-3.68 (t, 4H adjacent to O-

morpholine), 4.68 (s, 2H, N-CH2-N), 6.58-6.59 (m, 1H, furan-4H), 6.78-6.79 (d, J=3.56 Hz, 1H,

furan-3H), 7.64 (s, 1H, C=CH), 7.64-7.68 (d, J=4.52 Hz, 1H, furan-5H). LC-MS (m/z): 294

(M+).

The plausible mechanism for the formation of the above new Mannich base products probably

involved the formation of an alcohol intermediate (OH-intermediate) rather than imine from the

reaction between thiazolidine-2,4-dione derivatives (3) with formaldehyde. This intermediate

product then condensed with secondary amines to furnish the title compounds (4) in the reaction

that has not required a catalyst (Scheme 2).




11


Scheme 2: Mechanism for the formation of Mannich bases (4a-e)

3.2. Molecular Docking Study

In silico anti-inflammatory activity of compounds 4a-e was undertaken by studying the binding

and inhibition effects of ligands (4a-e) to the target COX-2 protein (PDB code: 1CX2) in which

the co-crystallized structure SC-558 was carefully removed using Discovery studio 2020 suite.

The docking results of the synthesized compounds (4a-e) and diclofenac used as the reference

drug are presented in Table 2.

Table 2. Docking results of thiazolidinedione-based Mannich base bearing furan/thiophene

moiety (4a-e).

Compound

No.

Binding

energy

Inhibitory

constant (μM)

No. of

H-bonds

H-Bond

4a -7.61 2.65 1 A:ARG120:HH::UNK0:O

4b -7.59 2.75 0 -

4c -6.64 13.53 1 A:TYR385:HH::UNK0:O

4d -6.72 11.81 0 -




12


4e -6.95 8.03 1 A:ARG120:HH::UNK0:O

Diclofenac -7.63 2.53 1 A:ARG120:HH::UNK0:O

The above results showed that two compounds 4a and 4b displayed good binding energy of

-7.61 kJ mol-1 and -7.59 kJ mol-1 respectively, which are comparable to the reference drug

diclofenac with -7.63 kJ mol-1. In addition to one conventional hydrogen bond interaction

between the oxygen atom of furan moiety in the compound 4a with NH of ARG 120 and one

carbon-hydrogen bond between the nitrogen atom of piperidine moiety with a CH group of VAL

523, the observed high binding affinity of compound 4a has been attributed to strong

hydrophobic interactions between 4a ligand with VAL 116, VAL 349, LEU 359, LEU 531, MET

522 and ALA 527 amino acids that maximized its interactions with the target binding site

(Figure 4a and 4b).

(a) (b)

Figure 4(a): Docked complex between the protein 1CX2 and ligand 4a; Figure 4(b):

Interacting residues between the protein 1CX2 and ligand 4a. The hydrogen bonds between

one of the O-atoms of the ligand with ARG 120 is shown in green dotted line.

The 1CX2-Diclorofenac complex is given in Figure 5(a) and the interacting residues in the

same complex are shown in Fig 5(b). Diclofenac displayed one conventional hydrogen bond

between the oxygen atom of the ligand with NH of ARG 120, and also showed strong




13


hydrophobic interactions with VAL 349, VAL 523, LEU352 and ALA 527 amino acids of the

target active site.

(a) (b)

Figure 5(a): Docked complex between protein 1CX2 and diclofenac ligand; Figure 5(b):

Interacting residues in 1CX2-Diclofenac complex. The hydrogen bond between one of the O-

atoms of the ligand with ARG 120 is shown in green dotted line. The observed results are in line

with Mousa et al. (2019) experiment in which Diclofenac inhibited the 1CX2 enzyme by binding

on ARG 120. Furthermore, molecular docking study results showed that each ligand molecule

displayed its own conformation, related to its IR spectrum that has fitted within the active site to

some extent. As a typical example, the IR spectrum of compound 4a showed the IR band at 1273

cm-1 for C-O-C (stretching) of the furan moiety. This furan-oxygen atom displayed one H-bond

with ARG 120 of the 1CX2 target protein. However, compound 4b which is lacking such a C-O-

C group of atoms did not display such IR band, hence unable to display any hydrogen bond with

the protein active site.

4. Conclusion

We successfully achieved the synthesis of novel series of thiazolidine-2,4-dione-based Mannich

base bearing furan/thiophene moiety (4a-e) in a reaction that did not require any acidic catalysts.

In silico docking studies of compounds (4a-e) on particular cyclooxygenase COX-2 enzyme

(PDB ID: 1CX2) have been evaluated in comparison with Diclofenac used as a reference drug.

The compounds 4a (5-(furan-2-ylmethylene)-3-(piperidin-1-ylmethyl)thiazolidine-2,4-dione)

and 4b (3-(Piperidin-1-ylmethyl)-5-(thiophen-2-ylmethylene)thiazolidine-2,4-dione) displayed




14


comparable docking energy to that of standard drug Diclofenac, and the present molecular

docking studies suggested that these compounds 4a and 4b are candidate ligands for restoring

inflammation and pain in conditions such as osteoarthritis, rheumatoid arthritis.

Acknowledgement

The authors are thankful to the Head, USIC-Mangalore University and SAIF-Panjab University

for providing facilities for spectral data.

Conflict of interest

The authors declare no conflict of interest

References

Afriza, D., Suriyah, W. H., & Ichwan, S. J. A. (2018). In silico analysis of molecular interactions

between the anti-apoptotic protein survivin and dentatin, nordentatin, and quercetin.

In Journal of Physics: Conference Series (Vol. 1073, No. 3, p. 032001).

https://doi.org/10.1088/1742-6596/1073/3/032001

Atzeni, F., Masala, I. F., & Sarzi-Puttini, P. (2018). A review of chronic musculoskeletal pain:

central and peripheral effects of diclofenac. Pain and therapy, 7(2), 163-177.

Bari, B.S., & D Firake, S. (2016). Exploring anti-inflammatory potential of thiazolidinone

derivatives of benzenesulfonamide via synthesis, molecular docking and biological

evaluation. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly

Current Medicinal Chemistry-Anti-Inflammatory and Anti-Allergy Agents), 15(1), 44-53.

https://doi.org/10.2174/1871523015666160524141630

Bakhle, Y. S. (1999). Structure of COX-1 and COX-2 enzymes and their interaction with

inhibitors. Drugs today, 35(4-5), 237-250. https://doi.org/10.1358/dot.1999.35.4-

5.552200

Berry, M., Fielding, B., & Gamieldien, J. (2015). Practical considerations in virtual screening

and molecular docking. Emerging trends in computational biology, bioinformatics, and

systems biology, 487-502. https://doi.org/10.1016/B978-0-12-802508-6.00027-2


https://doi.org10.1088/1742-6596/1073/3/032001

https://doi.org10.2174/1871523015666160524141630

https://doi.org10.1358/dot.1999.35.4-5.552200

https://doi.org10.1358/dot.1999.35.4-5.552200

https://doi.org/10.1016/B978-0-12-802508-6.00027-



15


Brune, K., & Patrignani, P. (2015). New insights into the use of currently available non-steroidal

anti-inflammatory drugs. Journal of pain research, 8, 105.

https://doi.org/10.2147/jpr.s75160

Ceriello, A. (2007). Thiazolidinediones as anti-inflammatory and anti-atherogenic

agents. Diabetes/Metabolism Research and Reviews, 24(1), 14-

26. https://doi.org/10.1002/dmrr.790

Chilamakuru, N., Shankarananth, V., Rajaskhar, K. K., & Singirisetty, T. (2013). Synthesis,

characterization and anti-tubercular activity of some new 3, 5-disubstituted-2, 4-

thiazolidinediones. Asian J Pharm Clin Res, 6(5), 29-33.

Durai Ananda Kumar, T., Swathi, N., Navatha, J., Subrahmanyam, C. V. S., & Satyanarayana,

K. (2015). Tetrabutylammonium bromide and K2CO3: an eco-benign catalyst for the

synthesis of 5-arylidene-1, 3-thiazolidine-2, 4-diones via Knoevenagel

condensation. Journal of Sulfur Chemistry, 36(1), 105-115.

Fokunang, C. N., Fokunang, E. T., Frederick, K., Ngameni, B., & Ngadjui, B. (2018). Overview

of non-steroidal anti-inflammatory drugs (NSAIDs) in resource limited

countries. MedCrave Online Journal of Toxicology , 4(1), 5-13.

https://doi.org/10.15406/mojt.2018.04.00081

Goldkind, L., & Laine, L. (2006). A systematic review of NSAIDs withdrawn from the market

due to hepatotoxicity: lessons learned from the bromfenac experience.

Pharmacoepidemiology and drug safety, 15(4), 213-220.

Ha, Y. M., Park, Y. J., Kim, J. A., Park, D., Park, J. Y., Lee, H. J., ... & Chung, H. Y. (2012).

Design and synthesis of 5-(substituted benzylidene) thiazolidine-2, 4-dione derivatives as

novel tyrosinase inhibitors. European journal of medicinal chemistry, 49, 245-252.

Holla, B. S., Kalluraya, B., & Sridhar, K. R. (1987). Syntheses of some 1-aryl-3-(5-nitro-2-

furyl)-2-propen-1-ones as potential antibacterial agents. Current Science, 585-588.

Huey, R., & Morris, G. M. (2008). Using AutoDock 4 with AutoDocktools: a tutorial. The

Scripps Research Institute, USA, 54-56.

Kar, K., Krithika, U., Basu, P., Kumar, S. S., Reji, A., & Kumar, B. P. (2014). Design, synthesis

and glucose uptake activity of some novel glitazones. Bioorganic chemistry, 56, 27-33.

https://doi.org/10.1016/j.bioorg.2014.05.006


https://doi.org10.2147/jpr.s75160

https://doi.org10.1002/dmrr.790

https://doi.org10.15406/mojt.2018.04.00081

https://doi.org10.1016/j.bioorg.2014.05.006



16


Meek, I. L., Van de Laar, M. A., & E Vonkeman, H. (2010). Non-steroidal anti-inflammatory

drugs: an overview of cardiovascular risks. Pharmaceuticals, 3(7), 2146-2162.

https://doi.org/10.3390/ph3072146.

Mishra, R., Jha, K. K., Kumar, S., & Tomer, I. (2011). Synthesis, properties and biological

activity of thiophene: A review. Der Pharma Chemica, 3(4), 38-54.

Mohanty, P., Aljada, A., Ghanim, H., Hofmeyer, D., Tripathy, D., Syed, T., Al-Haddad, W.,

Dhindsa, S., & Dandona, P. (2004). Evidence for a potent anti-inflammatory effect of

Rosiglitazone. The Journal of Clinical Endocrinology & Metabolism, 89(6), 2728-

2735. https://doi.org/10.1210/jc.2003-032103

Morris, G., D. Goodsell, M. Pique, W. Lindstrom, R. Huey, S. Forli, W. E. Hart, S. Halliday, R.

Belew, and A. J. Olson. "User guide autodock version 4.2." (2012).

Mousa, T. H., Rashid, A. M., & Mahdi, M. F. (2019). Design, Molecular docking, and Synthesis

of New Derivatives of Diclofenac with expected anti-inflammatory and selectivity to

COX-2 enzyme. Journal of Pharmaceutical Sciences and Research, 11(2), 531-539.

Naim, M. J., Alam, O., Alam, M. J., Hassan, M. Q., Siddiqui, N., Naidu, V. G. M., & Alam, M.

I. (2018). Design, synthesis and molecular docking of thiazolidinedione based benzene

sulphonamide derivatives containing pyrazole core as potential anti-diabetic

agents. Bioorganic chemistry, 76, 98-112. https://doi.org/10.1016/j.bioorg.2017.11.010

Ong, C. K. S., Lirk, P., Tan, C. H., & Seymour, R. A. (2007). An evidence-based update on

nonsteroidal anti-inflammatory drugs. Clinical medicine & research, 5(1), 19-34.

Rizvi, S. M. D., Shakil, S., & Haneef, M. (2013). A simple click by click protocol to perform

docking: AutoDock 4.2 made easy for non-bioinformaticians. EXCLI Journal, 12, 831-

857.

Rodríguez, L. A. G., & González-Pérez, A. (2005). Long-term use of non-steroidal anti-

inflammatory drugs and the risk of myocardial infarction in the general population. BMC

medicine, 3(1), 17. https://doi.org/10.1186/1741-7015-3-17

Sibbald, B. (2004). Rofecoxib (Vioxx) voluntarily withdrawn from market. Canadian Medical

Association Journal, 171(9), 1027-1028.

Srivastava, A. R., Bhatia, R., & Chawla, P. (2019). Synthesis, biological evaluation and

molecular docking studies of novel 3,5-disubstituted 2,4-thiazolidinediones


https://doi.org/10.3390/ph3072146

https://doi.org10.1210/jc.2003-032103

https://doi.org10.1016/j.bioorg.2017.11.010

https://doi.org10.1186/1741-7015-3-17



17


derivatives. Bioorganic chemistry, 89, 102993.

https://doi.org/10.1016/j.bioorg.2019.102993

Vostinaru, O. (2017). Adverse effects and drug interactions of the non-steroidal anti-

inflammatory drugs. InTech Open: Rijeka, Croatia, 17-31.

https://doi.org/10.5772/intechopen.68198

Zarghi, A., & Arfaei, S. (2011). Selective COX-2 inhibitors: a review of their structure-activity

relationships. Iranian journal of pharmaceutical research,10(4), 655-683.

Zhu, M., Flynt, L., Ghosh, S., Mellema, M., Banerjee, A., Williams, E., Panettieri, R. A., &

Shore, S. A. (2011). Anti-inflammatory effects of Thiazolidinediones in human airway

smooth muscle cells. American Journal of Respiratory Cell and Molecular

Biology, 45(1), 111-119. https://doi.org/10.1165/rcmb.2009-0445oc


https://doi.org/10.1016/j.bioorg.2019.102993

https://doi.org10.5772/intechopen.68198

https://doi.org10.1165/rcmb.2009-0445oc

facile synthesis, characterization and in silico docking

Documents